WO2018211517A1 - Formulations de protéines à haute concentration ayant une viscosité réduite - Google Patents

Formulations de protéines à haute concentration ayant une viscosité réduite Download PDF

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WO2018211517A1
WO2018211517A1 PCT/IN2017/050250 IN2017050250W WO2018211517A1 WO 2018211517 A1 WO2018211517 A1 WO 2018211517A1 IN 2017050250 W IN2017050250 W IN 2017050250W WO 2018211517 A1 WO2018211517 A1 WO 2018211517A1
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Prior art keywords
formulation
viscosity
acid
protein
range
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PCT/IN2017/050250
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English (en)
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Bhami Shenoy
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Bhami's Research Laboratory, Pvt. Ltd.
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Priority to US15/542,921 priority Critical patent/US10646569B2/en
Priority to EP17743098.0A priority patent/EP3624846A1/fr
Priority to SG11202003754YA priority patent/SG11202003754YA/en
Priority to CA3063324A priority patent/CA3063324A1/fr
Publication of WO2018211517A1 publication Critical patent/WO2018211517A1/fr
Priority to US16/788,218 priority patent/US11738082B2/en
Priority to US18/345,163 priority patent/US20240115702A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39591—Stabilisation, fragmentation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/70578—NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/06—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies from serum
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/22—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against growth factors ; against growth regulators
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/24—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
    • C07K16/241—Tumor Necrosis Factors
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2863—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for growth factors, growth regulators
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2875—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the NGF/TNF superfamily, e.g. CD70, CD95L, CD153, CD154
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2887—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against CD20
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/32—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against translation products of oncogenes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/32—Immunoglobulins specific features characterized by aspects of specificity or valency specific for a neo-epitope on a complex, e.g. antibody-antigen or ligand-receptor
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/52—Constant or Fc region; Isotype
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • concentration, low-viscosity formulation may be at least about 10 mg/mL, 50 mg/mL, 100 mg/mL, 150 mg/mL, 200 mg/mL, 250 mg/mL, 300 mg/mL, 350 mg/mL, 400 mg/mL, 450 mg/mL, 500 mg/mL or more.
  • the amount may be within a range bounded by a lower limit and an upper limit, the upper limit being larger than the lower limit.
  • the lower limit may be about 10 mg/mL, about 25 mg/mL, about 50 mg/mL, about 100 mg/mL, or about 150 mg/mL.
  • a method as described herein comprises preparing a liquid formulation comprising:
  • a buffer selected from the group consisting of phosphate buffers, acetate buffers, citrate buffers, histidine buffers, imidazole buffers, and combinations thereof;
  • a viscosity-reducing agent thiamine-HCl can be added to a protein agent with another viscosity-reducing agent selected from the group consisting of 2- aminopyrimadine, nicotinamide, nicotinic acid sodium salt, proline, glycine, and combinations thereof.
  • one viscosity-reducing agent is added to a protein agent formulation in a mole ratio to a second viscosity-reducing agent.
  • a mole ratio of a first viscosity-reducing agent to a second viscosity-reducing agent can be, for example, 1:0.001, 1 :0.002, 1:0.004, 1:0.005, 1 :0.010, 1:0.050, 1 :0.10, 1 :0.50, 1: 1, 1:2, 1 :5, 1: 10, 1:25, 1:50, 1 : 100, 1 :500, 1 : 1000, or higher.
  • the mole ratio may be bounded by a lower limit and an upper limit, the upper limit being larger than the lower limit.
  • the range when measured at 25° C, may be about 5 cP to about 35 cP. In some embodiments, when measured at 25° C, the range may be about 5 cP to about 30 cP. In some embodiments, when measured at 25° C, the range may be about 5 cP to about 25 cP. In some embodiments, when measured at 25° C, the range may be about 5 cP to about 20 cP. In some embodiments, when measured at 25° C, the range may be about 5 cP to about 15 cP. In some embodiments, when measured at 25° C, the range may be about 5 cP to about 10 cP.
  • FIGURE 1 depicts viscosity (in cP) as a function of protein concentration (in mg/mL) for Human Gamma Globulin (GLOBUCEL®) solution either in 25mM of Phosphate or Citrate or Histidine Buffer, pH 6.0 at 25 °C.
  • GLOBUCEL® Human Gamma Globulin
  • Phosphate buffer containing viscosity-reducing agents 6 mg/mL Tryptophan and 10 mg/mL Nicotinic acid (acid form).
  • an included CDR is substantially identical to a reference CDR in that it shows at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the reference CDR. In some embodiments an included CDR is substantially identical to a reference CDR in that it shows at least 96%, 96%, 97%, 98%, 99%, or 100% sequence identity with the reference CDR. In some embodiments an included CDR is substantially identical to a reference CDR in that at least one amino acid within the included CDR is deleted, added, or substituted as compared with the reference CDR but the included CDR has an amino acid sequence that is otherwise identical with that of the reference CDR.
  • an "antibody fragment” refers to a portion of an antibody or antibody agent as described herein, and typically refers to a portion that includes an antigen-binding portion or variable region thereof.
  • An antibody fragment may be produced by any means. For example, in some embodiments, an antibody fragment may be enzymatically or chemically produced by fragmentation of an intact antibody or antibody agent. Alternatively, in some embodiments, an antibody fragment may be recombinantly produced (i.e., by expression of an engineered nucleic acid sequence. In some embodiments, an antibody fragment may be wholly or partially synthetically produced.
  • Antibody half-life refers to the time in which a given amount of antibody or antibody agent, in vivo , is reduced to 50% of its initial concentration.
  • IgG typically has a half-life of about 21 days (though IgG3 has a half-life of only 7 days), while IgM, A, D, and E have typical half-lives of 10 days, 6 days, 3 days, and 2 days, respectively.
  • Branded As used herein, the term "branded" (when used in the context of regulatory approval) generally refer to a protein or biologic, are used interchangeably herein, to mean the single biological product licensed under section 351(a) of the U.S. Public Health Service Act (42 U.S.C. ⁇ 262).
  • Emulsifier As generally used herein, refers to a surface active agent which reduces interfacial tension between protein and a solution.
  • Hypertonic As generally used herein, the term “hypertonic” refers to a solution with a higher concentration of solutes than is present on the inside of the cell. When a cell is immersed into a hypertonic solution, the tendency is for water to flow out of the cell in order to balance the concentration of the solutes outside of the cell.
  • Isolated antibody refers to an antibody that has been identified and separated from a component of its natural environment. Contaminant components of its natural environment are materials that would interfere with diagnostic or therapeutic uses for the antibody, and may include enzymes, hormones, and other proteinaceous or non-pro teinaceous solutes. In certain embodiments, the antibody will be purified (1) to greater than a range of 95% to 99% by weight of antibody, or (2) to homogeneity by use of SDS-PAGE under reducing or non-reducing conditions using Coomassie blue or silver stain to visualize the antibody. Isolated, naturally occurring antibodies include an antibody in- situ within recombinant cells, since at least one component of the antibody's natural environment will not be present. Ordinarily, however, isolated antibodies will typically be prepared by at least one purification step.
  • Kinematic viscosity As used herein, the term “kinematic viscosity” refers to a measure of the rate at which momentum is transferred through a fluid. It is measured in Stokes (St). The kinematic viscosity is a measure of the resistive flow of a fluid under the influence of gravity. When two fluids of equal volume and differing viscosity are placed in identical capillary viscometers and allowed to flow by gravity, the more viscous fluid typically takes longer than the less viscous fluid to flow through the capillary. The dimension of kinematic viscosity is length /time. Commonly, kinematic viscosity is expressed in centiStokes (cSt). The SI unit of kinematic viscosity is mm2/s, which is equal to 1 cSt.
  • Osmolality refers to the total number of dissolved components per liter. Osmolarity is similar to molarity but includes the total number of moles of dissolved species in solution. An osmolarity of 1 Osm/L means there is 1 mole of dissolved components per L of solution. Some solutes, such as ionic solutes that dissociate in solution, will contribute more than 1 mole of dissolved components per mole of solute in the solution. For example, NaCl dissociates into Na + and CI in solution and thus provides 2 moles of dissolved components per 1 mole of dissolved NaCl in solution.
  • Physiological osmolarity is typically in the range of about 280 mOsm/L to about 310 mOsm/L.
  • the term "low-molecular-weight protein” generally excludes small peptides lacking the requisite of at least tertiary structure necessary to be classified as a protein.
  • the range may be about 150 kDa to about 400 kDa. In some embodiments, the range may be about 150 kDa to about 300 kDa. In some embodiments, the range may be about 150 kDa to about 250 kDa.
  • Protein molecular weight may be determined using standard methods known to one skilled in the art, including, but not limited to, mass spectrometry (e.g., ESI, MALDI) or calculation from known amino acid sequences and glycosylation. Proteins can be naturally occurring or non- naturally occurring, synthetic, or semi-synthetic.
  • Radiolabeh As generally used herein, the term “radiolabel” refers to the incorporation of a radiolabel to a protein, such as a therapeutic protein, or an antibody. In situations where the radiolabel has a short half-life, as with 1311 or 90Y, the radiolabel can also be therapeutic, e.g., used in radioimmunotherapies against cancers. Various methods of labeling polypeptides and glycoproteins are known in the art and may be used. Examples of labels include, but are not limited to, the following radioisotopes or radionucleotides: 3H, 14C, 15N, 35S, 90Y, 99Tc, l l lln, 1251, and 1311.
  • Reduced-viscosity formulation refers to a liquid formulation with a high concentration of a high- molecular- weight protein, such as a mAb, or a low-molecular- weight protein that is modified by the presence of one or more additives to lower the viscosity, as compared to a corresponding formulation that does not contain the viscosity-reducing additive(s).
  • a high- molecular- weight protein such as a mAb
  • a low-molecular- weight protein that is modified by the presence of one or more additives to lower the viscosity, as compared to a corresponding formulation that does not contain the viscosity-reducing additive(s).
  • Rheology As generally used herein, the term “rheology” refers to the study of the deformation and flow of matter.
  • a small molecule may have a characteristic core structural element (e.g., a macrocycle core) and/or one or more characteristic pendent moieties so that a variant of the small molecule is one that shares the core structural element and the characteristic pendent moieties but differs in other pendent moieties and/or in types of bonds present (single vs double, E vs Z, etc) within the core, a polypeptide may have a characteristic sequence element comprised of a plurality of amino acids having designated positions relative to one another in linear or three-dimensional space and/or contributing to a particular biological function, a nucleic acid may have a characteristic sequence element comprised of a plurality of nucleotide residues having designated positions relative to on another in linear or three-dimensional space.
  • a characteristic core structural element e.g., a macrocycle core
  • one or more characteristic pendent moieties so that a variant of the small molecule is one that shares the core structural element and the characteristic pendent moieties but
  • the range when measured at 25°C, the range may be about 5 cP to about 75 cP. In some embodiments, when measured at 25° C, the rang ;e may be about 5 cP to about 50 cP. In some embodiments, when measured at 25° C, the rang ;e may be about 5 cP to about 40 cP. In some embodiments, when measured at 25° C, the rang ;e may be about 5 cP to about 35 cP. In some embodiments, when measured at 25° C, the rang ;e may be about 5 cP to about 30 cP. In some embodiments, when measured at 25° C, the ran; ge may be about 5 cP to about 25 cP.
  • hypervariable region refers to amino acid residues from a complementarity-determining region or CDR (i.e., residues 24-34 (LI), 50-56 (L2) and 89-97 (L3) in the light chain variable domain and 31-35 (HI), 50-65 (H2) and 95- 102 (H3) in the heavy chain variable domain as described by Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md. (1991)).
  • "Framework" or FR residues are the remaining variable region residues other than the hypervariable region residues.
  • a protein agent is an antibody fragment.
  • a number of molecular fragments of antibody molecules have been isolated to date. These do not occur naturally, but are engineered from one or more complete antibody molecules. These fragments include Fab fragments (a single Fab that is isolated from a complete antibody by digestion with the enzyme papain), and F(ab')2 fragments (two Fabs covalently-bound to each other, produced by digesting the antibody with the enzyme pepsin). Fab fragments are monospecific, while F(ab')2 fragments are bispecific. Recently, a number of engineered antibody fragments have been introduced.
  • chimeric antibodies comprise framework regions from one antibody and CDR regions from another antibody.
  • Chimeric antibodies also include those which comprise CDR regions from at least two different human antibodies.
  • Humanized antibodies typically contain approximately 90% (or more) human amino acid sequences. In this scenario, the only murine sequences present are those for a hypervariable region (that are the actual antigen-binding sites contained within a variable region). Humanized antibodies have minimal mouse
  • Adalimumab HUMIRA®, ABP501 (Amgen), GP2017 (Novartis)
  • the range may be about 5.0 to 8.0. In some embodiments, the range may be about 5.8 to 7.4. In some embodiments, the range may be about 6.2 to 7.0.
  • a viscosity-reducing agent is or comprises one or more of nicotinic acid (acid form), nicotinamide (niacinamide), nicotinic acid sodium salt, benzyl nicotinate, inositol hexanicotinate, nicotinyl alcohol ( ⁇ -pyridyl carbinol), xanthine nicotinate, methyl nicotinate, ethyl nicotinate, propyl nicotinate, isopropyl nicotinate, butyl nicotinate, isoamyl nicotinate, hexyl nicotinate, phenyl nicotinate, gauiacyl nicotinate, xanthinol nicotinate, nicametate citrate, nicotinuric acid, nicotinyl hydroxamate, tocopheryl nicotinate
  • a viscosity-reducing is or comprises one or more of a water-soluable vitamin group including L-Pantothenic Acid hemicalcium salt, L-ascorbic acid, Thiamine-HCl, Rutin Hydrate, Riboflavin, Folic Acid, pyridoxine, Biotin, Pantoic acid, S- benzoylthiamine, Pyridoxal, Pyridoxamine, Niacin, and combinations thereof.
  • a water-soluable vitamin group including L-Pantothenic Acid hemicalcium salt, L-ascorbic acid, Thiamine-HCl, Rutin Hydrate, Riboflavin, Folic Acid, pyridoxine, Biotin, Pantoic acid, S- benzoylthiamine, Pyridoxal, Pyridoxamine, Niacin, and combinations thereof.
  • Polyethylene glycol Polyethylene glycol, branched PEG, PolyPEG®, and combinations thereof.
  • a viscosity-reducing agent includes at least one carboxylic acid.
  • a carboxylic acid may be in the form of an alkaline or alkaline earth metal salt, such as lithium, sodium, potassium, magnesium, and calcium salt.
  • a viscosity-reducing agent may include lactobionic acid, glucuronic acid, 1- aminocyclohexane carboxylic acid, biotin, brocrinat, cyclopentane propionic acid,
  • a viscosity-reducing agent is selected from a third set of viscosity-reducing agents, which third set includes each of Nicametate Citrate, Nicotinuric Acid, Ethanol, Nicotinyl Hydroxamate, Ornidazole, Piperazine, or Methylisothiazolinone, and combinations thereof.
  • the range may be about 1 mM to about 200 mM. In som embodiments, the range may be about 1 mM to about 100 mM. In some embodiments, the range may be about 5 mM to about 1000 mM. In some embodiments, the range may bea bout 5 mM to about 500 mM. In some embodiments, the range may be about 5 mM to about 200 mM. In some embodiments, the range may be about lOmM to about 200 mM. In some embodiments, the range may be about lOmM to about 150 mM. In some embodiments the range may be about lOmM to about 100 mM. In some embodiments the range may be about 15 mM to about 75 mM. In some embodiments, the range may be about 15 mM to about 25 mM.
  • a viscosity-reducing agent is or comprises one or more of
  • a protein agent formulation with an aggregation-reducing agent can have a decreased aggregation that is at least about 5% less than the analogous control or reference formulation without an aggregation-reducing agent, when measured under the same conditions.
  • a protein agent formulation may have an aggregation measurement that may be, for example, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or even more than 90% less than the analogous control protein agent formulation without an aggregation-reducing agent.
  • the percentage decrease in aggregation once the aggregation-reducing agent is incorporated maybe be within a range bound by a lower limit and an upper limit, the upper limit being larger than the lower limit.
  • the range maybe be about 50% to about 99% decrease in aggregation. In some embodiments, the range maybe be about 60% to about 99% decrease in aggregation. In some embodiments, the range maybe be about 70% to about 99% decrease in aggregation. In some embodiments, the range maybe be about 80% to about 99% decrease in aggregation. In some embodiments, the range maybe be about 90% to about 99% decrease in aggregation.
  • an aggregation-reducing agent is or comprises one or more of nicotinic acid, caffeine citrate, caffeine nicotinate, caffeine, octyl- ⁇ -D-glucopyranoside, and n-dodecyl-P-D-maltoside and optionally in combination with one or more of arginine, tryptophan, histidine, proline, cysteine, methionine, ⁇ -alanine, Potassium Glutamate, Arginine Ethylester, lysine, aspartic acid, glutamic acid, glycine, DTPA (diethylenetriaminepentaacetic acid), EGTA(aminopolycarboxylic acid), EDTA (Ethylenediaminetetraacetic acid), hydroxy propyl beta (HP-Beta) cyclodextrins, hydroxy propyl gamma (HP-Gamma) cyclodextr
  • the range may be about 0% to about 2.5% (w/v). In some embodiments the range may be about 0% to about 2% (w/v). In some embodiments the range may be about 0% to about 1.5% (w/v). In some embodiments the range may be about 0% to about 1% (w/v). In some embodiments the range may be about 0% to about 0.5% (w/v). In some embodiments, the range may be about 0% to about 0.4%. In some embodiments, the range may be about 0% to about 0.3%. In some embodiments, the range may be about 0% to about 0.2%. In some embodiments, the range may be about 0% to about 0.1%.
  • castor oil diacetylated monoglycerides, diethyl phthalate, glycerin, mono- and di-acetylated monoglycerides, polyethylene glycol, propylene glycol, triacetin and triethyl citrate), polymer membranes (e.g. cellulose acetate), solvents (e.g.
  • an aqueous protein agent formulation has a viscosity that is at least about 30% less than the analogous control or reference formulation without a viscosity-reducing agent, when measured under the same conditions.
  • a protein agent formulation has a viscosity that may be, for example, at least 35%, 40%, 50%, 60%, 70%, 80%, 90%, or even more than 90% less than the analogous control protein agent formulation without the viscosity-reducing agent(s).
  • the percentage decrease in viscosity once the viscosity-reducing agent is incorporated maybe be within a range bound by a lower limit and an upper limit, the upper limit being larger than the lower limit.
  • the amount may be within a range bounded by a lower limit and an upper limit, the upper limit being larger than the lower limit.
  • the lower limit may be about 0.10 mL, about 0.25 mL, about 0.50 mL, about 0.75 mL, or about 1.0 mL.
  • the range may be about 0.10 mL to about 1.6 mL. In some embodiments, the range may be about 0.10 mL to about 1.4 mL. In some embodiments, the range may be about 0.10 mL to about 1.2 mL. In some embodiments, the range may be about 0.10 mL to about 1.0 mL. In some embodiments, the range may be about 0.10 mL to about 0.75 mL. In some embodiments, the range may be about 0.10 mL to about 0.50 mL. In some embodiments, the range may be about 0.10 mL to about 0.25 mL. In some embodiments, the range may be about 0.10 mL to about 5.0 mL.
  • a viscosity gradient of a protein agent formulation may be, for example, less than about 5.0 cP mL/mg, 3.0 cP mL/mg, 2.0 cP mL/mg, 1.5 cP mL/mg, 1.0 cP mL/mg, 0.8 cP mL/mg, 0.6 cP ml/mg, 0.5 cP mL/mg, 0.1 cP mL/mg, 0.05 cP mL/mg, 0.02 cP mL/mg, or lower for a protein agent formulation with a protein concentration between 10 mg/mL and 5,000 mg/mL.
  • the upper limit may be about 75 mM, about 100 mM, about 150 mM, about 200 mM, about 300 mM, about 400 mM, about 500 mM, about 600 mM, about 700 mM, about 800 mM, about 900 mM, or about 1000 mM.
  • the range may be about 1 mM to about 1000 mM.
  • the range may be about lOmM to about 200 mM.
  • a tonicity modifier is sodium chloride within a concentration range of 0 mM to 200 mM.
  • the pH of a high concentration, low viscosity protein agent pharmaceutical formulation may be, for example, at least about 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, and 10.0 or higher.
  • the upper limit may be about 6.1, about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, about 7.0, about 7.1, about 7.2, about 7.3, about 7.4, about 7.5, about 7.6, about 7.7, about 7.8, about 7.9, about 8.0, about 8.1, about 8.2, about 8.3, about 8.4, about 8.5, about 8.6, about 8.7, about 8.8, about 8.9, about 9.0, about 9.1, about 9.2, about 9.3, about 9.4, about 9.5, about 9.6, about 9.7, about 9.8, about 9.9, or about 10.0.
  • the range may be about 3.0 to about 10.0. In some embodiments, the range may be about 4.0 to about 10.0.
  • the route of administration of a protein agent formulation is subcutaneous (SC) and/or intramuscular (IM) injection.
  • SC subcutaneous
  • IM intramuscular
  • benzyl alcohol may also be added to a protein agent formulation.
  • Further examples of components that may be employed in a pharmaceutical formulation are presented in Remington's Pharmaceutical Sciences, 16 th Ed., Mack Publishing Company, Easton, Pa., 1980, and in the Handbook of Pharmaceutical Excipients, published jointly by the American Pharmaceutical Association and the Pharmaceutical Society of Great Britain.
  • a therapeutic protein agent formulation is an aqueous formulation that allows for stable, long-term storage. These formulations are useful, in part, because they are more convenient for the patient to use, as these formulations do not require any extra steps such as rehydrating.
  • a “solution” or “liquid formulation” is meant to mean a liquid preparation that contains one or more chemical substances dissolved in a suitable solvent or mixture of mutually miscible solvents. Reconstitution is the dissolution of lyophilized therapeutic protein agent formulations or compositions in appropriate buffers or pharmaceutical formulations.
  • the range of moisture content after lyophilization may be about 0.1% to about 2% by weight. In some embodiments, the range of moisture content after lyophilization may be about 0.1% to about 1.5% by weight. In some embodiments, the range of moisture content after lyophilization may be about 0.1% to about 1% by weight. In some embodiments, the range of moisture content after lyophilization may be about 0.1% to about 0.5% by weight.
  • a therapeutic protein agent powder can be optionally combined with carriers or surfactants.
  • a suitable carrier agent is can include carbohydrates (e.g. monosaccharides such as fructose, galactose, glucose, and sorbose), disaccharides (e.g. lactose and trehalose),
  • the range may be about 100 mg/mL to about 350 mg/mL. In some embodiments, the range may be about 100 mg/mL to about 300 mg/mL. In some embodiments, the range may be about 100 mg/mL to about 250 mg/mL. In some embodiments, the range may be about 100 mg/mL to about 200 mg/mL.
  • Purification of a protein agent to be formulated may be conducted by any suitable technique known in the art that can include ethanol, polyethylene glycol or ammonium sulfate precipitation, ion-exchange chromatography, affinity chromatography, adsorption
  • a buffer exchanged protein agent solution containing excipients and a viscosity- reducing agent is then concentrated using the TFF system.
  • a protein agent solution containing a viscosity-reducing agents and other excipients can be dried by air drying, spray drying, lyophilization or vacuum drying. Drying is carried out for a minimum of about 1 hour to a maximum of about 72 hours after incubation, until the moisture content of the final product is below about 5% to about 10% by weight. Finally, micromizing (reducing the size) of a cake can be performed if necessary.
  • useful radiolabels can include 3H, 14C, 15N, 35S, 90Y, 99Tc, l l lln, 1251, 1311. Practically, however, in vivo use in radiotherapies would limit a radiolabel to 1311, 90 Y, or any other radiolabels defined by a short half-life.
  • the monoclonal antibody Rituximab see Example 1 has been labeled with 90Yttrium (90Y), in order to be used for
  • the range may be about 100 mg to about 1000 mg. In some embodiments, the range may be about 100 mg to about 800 mg. In some embodiments, the range may be about 100 mg to about 600 mg. In some embodiments, the range may be about 100 mg to about 400 mg. In some embodiments, the range may be about 100 mg to about 200 mg.
  • bioavailability and an increased stability of a protein agent in a low-viscosity, high protein agent concentration formulation more stable blood levels of an administered therapeutic protein agent can be achieved, potentially with lower dosages.
  • the slow and constant release capabilities afforded by the present invention advantageously permit reduced dosages, due to more efficient delivery of an active therapeutic protein agent. Significant cost savings may be achieved by using high concentration, low-viscosity therapeutic protein agents formulations described herein.
  • a viscosity-reducing agent may be used to prepare a dosage unit formulation suitable for reconstitution to make a liquid pharmaceutical formulation for subcutaneous or intramuscular injections.
  • a dosage unit may contain a dry powder of one or more protein agents; one or more viscosity-reducing agents; and other excipients.
  • Protein agents that are present in the dosage unit such that after reconstitution in a pharmaceutically acceptable solvent, a resulting formulation has a protein agent concentration that may be at least about 10 mg/mL, 50 mg/mL, 100 mg/mL, 150 mg/mL, 200 mg/mL, 250 mg/mL, 300 mg/mL, 350 mg/mL, 400 mg/mL, 450 mg/mL, 500 mg/mL or more.
  • a reconstituted formulation may have an absolute viscosity that when measured at 25° C, may be, for example, about 100 cP, 75 cP, 50 cP, 45 cP, 40 cP, 35 cP, 30 cP, or lower.
  • the amount may be within a range bounded by a lower limit and an upper limit, the upper limit being larger than the lower limit.
  • the lower limit when measured at 25° C, the lower limit may be about 1 cP, about 5 cP, about 10 cP, or about or 15 cP.
  • a dosage unit of a therapeutic protein agent may be, for example, at least 50 mg, 100 mg, 120 mg, 140 mg, 160 mg, 180 mg, 200 mg, 220 mg, 240 mg, 260 mg, 280 mg, 300 mg 350 mg, 400 mg, 500 mg, or more.
  • the amount may be within a range bounded by a lower limit and an upper limit, the upper limit being larger than the lower limit.
  • the lower limit may be about 50 mg, about 100 mg, about 120 mg, about 140 mg, about 160 mg, about 180 mg, about 200 mg, about 220 mg, about 240 mg, about 260 mg, about 280 mg, or about 300 mg.
  • the lower limit may be about 0.01%, about 0.1%, about 1%, about 10%, about 20%, or about 30% (w/w).
  • the upper limit may be about 40%, about 50%, about 60%, about 70% about 80%, about 90%, or about 99% (w/w).
  • the range may be about 0.01% to about 99% (w/w).
  • the range may be about 0.1% to about 99% (w/w).
  • the range may be about 1% to about 99% (w/w).
  • the range may be about 10% to about 99% (w/w).
  • the range may be about 20% to about 99% (w/w).
  • a dosage of a protein agent formulation may be administered for example, at least once every two days, every three days, every five days, every 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, or more.
  • the amount of time may be within a range bounded by a lower limit and an upper limit, the upper limit being larger than the lower limit.
  • the lower limit may be about two days, about three days, about five days, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, or about 7 weeks.
  • the range may be about 0 cm to about 100 cm. In some embodiments, the range may be about 1.0 cm to about 100 cm. In some embodiments, the range may be about 2.0 cm to about 100 cm. In some embodiments, the range may be about 2.5 cm to about 100 cm. In some embodiments, the range may be about 5.0 cm to about 100 cm. In some embodiments, the range may be about 10 cm to about 100 cm. In some embodiments, the range may be about 20 cm to about 100 cm. In some embodiments, the range may be about 50 cm to about 100 cm. In some embodiments, the range may be about 75 cm to about 100 cm.
  • a viscosity-reducing formulation can be provided as a solution or in a dosage unit form wherein a protein agent is lyophilized in one vial, with or without a viscosity-reducing agent and other excipients, and a solvent, with or without a viscosity-reducing agent and other excipients, is provided in a second vial.
  • a solvent is added to a protein agent shortly before or at the time of injection to ensure uniform mixing and dissolution.
  • a low- viscosity protein agent formulation comprising a high concentration protein agent may be delivered to humans, animals, or plants at a desired site of delivery according to this invention.
  • delivery may include use of devices, such as implant-capable devices, or may involve other microparticulate protein delivery systems. Such systems may allow for slow or controlled release of a protein agent in the subject.
  • a pharmaceutical, veterinary, or prophylactic preparation comprising a high concentration, low viscosity therapeutic protein agent formultion, may also be administered by a vehicle that can include tablets, liposomes, granules, spheres, microparticles, microspheres, capsules, and combinations thereof.
  • a high concentration, low-viscosity therapeutic protein agent formulation may be administered alone, as part of a pharmaceutical, personal care or veterinary preparation, or as part of a prophylactic preparation, with or without an adjuvant.
  • a protein agent formulation may be administered by a parenteral or an enteral route.
  • a high concentration, low- viscosity protein agent formulation may be prepared in a tablet form.
  • Such tablets constitute a liquid-free, dust-free form for storage of a therapeutic protein agent, which is then easily handled and allows for retention of an acceptable level of activity or potency.
  • a therapeutic protein agent formulation may be appropriate for a variety of modes of administration, including parenteral administration.
  • a parenteral route of administration is selected from the group consisting of intramuscular, intraperitoneal, intradermal, intravitreal, epidural, intracerebral, intra-arterial, intraarticular, intra-cavernous, intra-lesional, intraosseous, intraocular, intrathecal, transdermal, trans-mucosal, extra- amniotic administration, and combinations thereof.
  • the lower limit may be about 10%, about 15%, about 20%, or about 25% less force than the control formulation upon injection.
  • the upper limit may be about 30%, about 35%, about 40%, about 45%, or about 50% less force than the control formulation upon injection.
  • the range may be about 10% to about 60% decrease in injection force. In some embodiments, the range may be about 10% to about 55% decrease in injection force. In some embodiments, the range may be about 10% to about 50% decrease in injection force. In some embodiments, the range may be about 15% to about 50% decrease in injection force. In some embodiments, the range may be about 20% to about 50% decrease in injection force. In some embodiments, the range may be about 25% to about 50% decrease in injection force.
  • the range may be about 30% to about 50% decrease in injection force. In some embodiments, the range may be about 35% to about 50% decrease in injection force. In some embodiments, the range may be about 40% to about 50% decrease in injection force. In some embodiments, the range may be about 45% to about 50% decrease in injection force as compared to standard control formulations without the viscosity- reducing agent(s) but otherwise under the same injection conditions.
  • a protein agent formulation possesses "Newtonian flow characteristics," defined as having a viscosity that is substantially independent of shear rate.
  • a protein agent formulations can be readily injected through a needle of about 22-32 gauge. In some embodiments, an injection is administered via a 27 gauge needle and the injection force is less than 30 N.
  • a formulation can be administered, in most cases, using a very small gauge needle, for example, between 27 and 31 gauge, preferably 29 gauge and more preferably 31 gauge needle.
  • a protein agent formulation including a reconstituted formulation
  • a protein agent formulation can also be preheated in a separate warming unit prior to filling a syringe.
  • a syringe heater is a device which often contains one or more slots for holding a syringe filled with a protein agent formulation, and a controlling system to heat, monitor and maintain a temperature range of a formulation-filled syringe at a given specific temperature range.
  • a therapeutic use for a high concentration, low viscosity protein agent formulation can include treatment and/or detection of cancers such as breast cancer, gastric cancer, Non-Hodgkin's Lymphoma, urothelial carcinoma & solid tumors, Metastatic colorectal cancer, Non-squamous non-small cell lung cancer, Metastatic breast cancer, Hodgkin lymphoma, Biliary cancer, Acute myeloid Leukemia, prostate cancer, multiple myeloma, solid tumors of bone, neuroblastoma, pancreatic cancer, acute myelogenous leukemia, metastatic melanoma, metastatic squamous non-small cell cancer, Anaplastic astrocytoma; Brain cancer, Glioblastoma, Glioma, Head and neck cancer, Merkel cell carcinoma, Nasopharyngeal cancer, Oesophageal cancer, Hepatocellular carcinoma , refractory euroblastoma, Osteosarcom
  • cancers such as breast cancer
  • a therapeutic use for a high concentration, low viscosity protein agent formulation can include treatment and/or dectection of an infectious disease like Clostridium difficile infection, respiratory syncytial virus (RSV) disease, Anthrax, Flu virus infection, Influenza Virus infection, Hepatitis B virus infection, Rabies virus infection, invasive Candida infection, bacterial septic shock, HIV infection, Nosocomial pneumonia, Staphylococcal infections, STEC (Shiga- like toxin-producing Escherichia coli or E. coli serotype 0121) infection causing diarrhea and HUS (hemolytic-uremic syndrome), Cytomegalovirus, Botulism, Ebola Virus, and combinations thereof.
  • an infectious disease like Clostridium difficile infection, respiratory syncytial virus (RSV) disease, Anthrax, Flu virus infection, Influenza Virus infection, Hepatitis B virus infection, Rabies virus infection, invasive Candida infection, bacterial septic shock, HIV infection, Nosocomial pneumonia
  • a therapeutic use for a high concentration, low viscosity protein agent formulation can include treatment and/or dectection of a respiratory disorder such as asthma,chronic idiopathic urticaria,acute bronchospasm or status asthmaticus, Chronic obstructive pulmonary disease, and combinations thereof.
  • a respiratory disorder such as asthma,chronic idiopathic urticaria,acute bronchospasm or status asthmaticus, Chronic obstructive pulmonary disease, and combinations thereof.
  • the collected protein sample was stored at 4°C O/N.
  • the final concentration of HGG in solution was determined by measuring absorbance at 280 nm in a UV visible spectrophotometer against the respective buffer (which does not contain any HGG).
  • Reported protein concentrations represent the range of all protein samples in each Table or Figure. Specifically, reported values are the median plus or minus half the range.
  • the protein concentrations were experimentally determined using the extinction coefficient of The viscosities of the solution were
  • the present example describes the effect of various amino acids or amino acid derivatives on the viscosity of aqueous solutions of Human Gamma Globulin.
  • HGG human gamma globulin
  • GLOBUCEL® 50 mg/mL containing pharmaceutical excipients (Maltose) was dialyzed against water for 24 hr at 4°C with three changes.
  • phosphate/citrate/histidine Buffer was added from the stock concentration of 1000 mM phosphate/citrate/histidine buffer, pH 6.0 to get a final concentration of 25 mM.
  • the present example describes the effect of various nucleosides, nucleotides or derivatives on the viscosity of aqueous solutions of Human Gamma Globulin.
  • the solution were measured either using a Cambridge Viscometer, VISCOlab5000 using 70 ⁇ L ⁇ of sample at 25°C or using a DV2T cone and plate viscometer using 1.5 mL of sample at 25°C at extrapolated zero shear rate.
  • the present example describes the effect of various vitamins and its derivatives on the viscosity of aqueous solutions of Human Gamma Globulin.
  • the solution were measured either using a Cambridge Viscometer, VISCOlab5000 using 70 ⁇ L ⁇ of sample at 25°C or using a DV2T cone and plate viscometer using 1.5 mL of sample at 25°C at extrapolated zero shear rate.
  • Table 13 The data in Table 13, Table 14 and Table 15 demonstrate the viscosity-reducing effect of various vitamins, salts of vitamins or derivatives of vitamins, on Human gamma globulin (GLOBUCEL®) in either phosphate or citrate or histidine buffer.
  • GLOBUCEL® Human gamma globulin
  • the viscosities of the solution were measured either using a Cambridge Viscometer, VISCOlab5000 using 70 ⁇ L ⁇ of sample at 25°C or using a DV2T cone and plate viscometer using 1.5 mL of sample at 25°C at extrapolated zero shear rate.
  • Example 9 Viscosity-Reducing effect of Nicotinic acid (acid form), a viscosity-reducing reagent, as a function of nicotinic acid (acid form) concentration on aqueous solution of Human Gamma Globulin (HGG).
  • the present example describes the effect of different concentrations of a viscosity-reducing agent nicotinic acid (acid form) on the viscosity of aqueous solutions of Human Gamma Globulin.
  • the final concentration of HGG in solution was determined by measuring absorbance at 280 nm in a UV visible spectrophotometer against the histidine buffer containing viscosity-reducing agent alone (which does not contain any HGG) for measuring the protein concentration in excipient containing sample; and for HGG without any excipient, buffer alone (without any excipient) was used as a blank to determine the protein concentration.
  • Reported protein concentrations represent the range of all protein samples in each Table or Figure. Specifically, reported values are the median plus or minus half the range.
  • the protein concentrations were experimentally determined using the extinction coefficient of 1.4 (A at 280 nm.
  • the solution were measured either using a Cambridge Viscometer, VISCOlab5000 using 70 ⁇ L ⁇ of sample at 25°C or using a DV2T cone and plate viscometer using 1.5 mL of sample at 25°C at extrapolated zero shear rate.
  • the data in Table 19 demonstrate the viscosity reducing effect of different concentrations of viscosity-reducing agent nicotinic acid (acid form) on Human Gamma Globulin (HGG) in histidine buffer.
  • the viscosity-reducing effect of nicotinic acid (acid form) is seen to rise from 1.7 to 3.5 fold with increasing concentrations of nicotinic acid (acid form).
  • the data in Table 19 show that the higher the concentration of viscosity-reducing agent, the greater the viscosity-reducing effect, at least within the nicotinic acid (acid form) concentration range tested.
  • the solubility of nicotinic acid (acid form) decreases when the concentration of nicotinic acid (acid form) increased above 18 mg/mL.
  • Example 10 The Effect of Temperature on Viscosity of Aqueous Solution of Human Gamma Globulin Formulated with Viscosity-Reducing agent Nicotinic acid (acid form).
  • the collected protein sample was stored at 4°C O/N.
  • the final concentration of HGG in solution was determined by measuring absorbance at 280 nm in a UV visible spectrophotometer against the histidine buffer containing viscosity-reducing agent alone (which does not contain any HGG) for measuring the protein concentration in excipient containing sample; and for HGG without any excipient, buffer alone (without any excipient) was used as a blank to determine the protein concentration.
  • the collected HGG sample was divided into two fractions. One fraction was used as excipient, nicotinic acid (acid form) containing sample; the other fraction was dialysed extensively against 25 mM histidine buffer, pH 6.0 for 24 hr with three changes to remove viscosity-reducing agent, nicotinic acid (acid form) and concentrated using Vivaspin centrifugal concentrators as described above.
  • HGG human gamma globulin
  • GLOBUCEL® 50 mg/mL containing pharmaceutical excipients (Maltose) was dialyzed against water for 24 hr at 4°C with three changes.
  • phosphate buffer was added from the stock concentration of 1000 mM phosphate buffer, pH 6.0 to get a final concentration of 25 mM.
  • the excipient/viscosity-reducing reagent containing HGG was
  • HGG human gamma globulin
  • GLOBUCEL® 50 mg/mL containing pharmaceutical excipients (Maltose) was dialyzed against water for 24 hr at 4°C with three changes.
  • phosphate/citrate/histidine buffer was added from the stock concentration of 1000 mM phosphate/citrate/histidine buffer, pH 6.0 to get a final concentration of 25 mM.
  • the excipient containing HGG was concentrated to a final volume of less than 150 ⁇ L ⁇ using Vivaspin centrifugal concentrators (Sartorius).
  • the collected protein sample was stored at 4°C O/N.
  • the final concentration of HGG in solution was determined by measuring absorbance at 280 nm in a UV visible
  • spectrophotometer against the phosphate/citrate/histidine containing viscosity-reducing agents alone (which does not contain any HGG) for measuring the protein concentration in excipient containing sample; and for HGG without any excipients, buffer alone (without any excipients) was used as a blank to determine the protein concentration.
  • Reported protein concentrations represent the range of all protein samples in each Table or Figure. Specifically, reported values are the median plus or minus half the range. The protein concentrations were experimentally determined using the extinction coefficient of 1.4 [ 280 nm. The
  • Example 15 A Comparison of Different Methods for Measuring Viscosity of Human Gamma Globulin.
  • the collected protein sample was stored at 4°C O/N.
  • the final concentration of HGG in solution was determined by measuring absorbance at 280 nm in a UV visible spectrophotometer against the citrate-phosphate buffer containing viscosity-reducing agent alone (which does not contain any HGG).
  • Reported protein concentrations represent the range of all protein samples in each Table or Figure. Specifically, reported values are the median plus or minus half the range.
  • the protein concentrations were experimentally determined using the extinction coefficient of 1.4 at 280 nm.
  • ViscoLab 5000 equipped with a piston covering the range from 5 - 100 cP was used and for viscosities above 100 cP, ViscoLab 4000 equipped with a piston covering the range 50 - 1000 cP was used.

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Abstract

La présente invention, entre autres, concerne des formulations d'agent protéiques thérapeutiques à faible viscosité et à concentration élevée.
PCT/IN2017/050250 2017-05-16 2017-06-20 Formulations de protéines à haute concentration ayant une viscosité réduite WO2018211517A1 (fr)

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SG11202003754YA SG11202003754YA (en) 2017-05-16 2017-06-20 High concentration protein formulations with reduced viscosity
CA3063324A CA3063324A1 (fr) 2017-05-16 2017-06-20 Formulations de proteines a haute concentration ayant une viscosite reduite
US16/788,218 US11738082B2 (en) 2017-05-16 2020-02-11 High concentration protein formulations with reduced viscosity
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US10646569B2 (en) 2017-05-16 2020-05-12 Bhami's Research Laboratory, Pvt. Ltd. High concentration protein formulations with reduced viscosity
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WO2022231481A1 (fr) * 2021-04-27 2022-11-03 Joint Stock Company "Biocad" Composition pharmaceutique de pembrolizumab et son utilisation
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